Primary Gastrointestinal Stromal Tumor of the Liver in an Anorectal Melanoma Survivor: a Case Report

2366 ONCOLOGY LETTERS 10: 2366-2370, 2015

Primary gastrointestinal stromal tumor of the liver in an anorectal melanoma survivor: A case report

YUNG‑YEH SU1, NAI‑JUNG CHIANG2,3, CHUN‑CHIEH WU4 and LI‑TZONG CHEN1-3

1Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807; 2National Institute of Cancer Research, National Health Research Institutes, Tainan 704; 3Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 701; 4Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

Received May 17, 2014; Accepted February 10, 2015

DOI: 10.3892/ol.2015.3561

Abstract. The majority of gastrointestinal stromal Introduction tumors (GISTs) arise in the stomach and small intestine; primary GIST of the liver is extremely rare. GISTs share Anorectal melanoma, the third most common site of mucosal specific immunohistological features with melanoma, there- melanoma, is a rare tumor with an incidence rate of 1.7 cases per fore, determining a definitive diagnosis can be difficult. million in the global population (1). Surgery, including abdomi- However, electron microscopy can be used to aid the differen- noperineal resection (APR) or wide local excision (WLE), is tial diagnosis of GIST. The present study reports the first case the primary treatment strategy for localized disease; however, of a KIT/platelet‑derived growth factor receptor α (PDGFRA) these two surgical approaches result in similarly poor clinical wild‑type, primary GIST arising from the liver in a long‑term outcomes, with five‑year recurrence rates of 79 and 81% survivor of anorectal melanoma. The patient underwent APR following APR and WLE, respectively (2). Furthermore, the for treatment of malignant melanoma of the anorectum in five‑year overall survival rate following curative resection ranges 2001 with no adjuvant therapy and remained disease-free until from 15 to 22%, with the majority of patients succumbing to 2009. In 2009, the patient presented with a solitary, rapidly recurrent disease. Recurrence predominantly occurs in the liver, growing hypervascular liver tumor, which was subsequently followed by the lung and brain (3,4). diagnosed as a primary GIST of the liver. Imatinib treatment Gastrointestinal stromal tumors (GISTs), characterized (400 mg/day) was initially administered for two months, by the expression of cluster of differentiation (CD) 117 and however, disease progression occurred. Therefore, the patient a high incidence of KIT or platelet‑derived growth factor underwent chemotherapy with doxorubicin (50 mg/m2) receptor α (PDGFRA) mutations, are uncommon tumors with and cisplatin (50 mg/m2) every three weeks. Although this an incidence range of 6‑15 cases per million individuals (5). temporarily resulted in stable disease, progression occurred The majority of GISTs arise in the stomach and small intes- five months later. Finally, oral sunitinib (37.5 mg/day) was tine, and GISTs originating from the esophagus, colon and administered; however, the patient succumbed to the disease extra‑gastrointestinal organs, such as the retroperitoneum and one month later. Despite the current GIST patient exhibiting liver, are rare (6). To the best of our knowledge, only five cases a poor response to imatinib, the present study highlights the of primary hepatic GIST have previously been reported in the importance of considering a second primary malignancy and English literature (7‑11). The most common KIT mutation sites performing immunohistochemical analysis upon the occur- involve exon 11 (66.1%) followed by exon 9 (13%); however, rence of a newly developed lesions in long‑term remission 12% of cases exhibit no detectable KIT mutation and are there- cancer survivors. fore categorized as KIT wild‑type GISTs (12). The present study reports the case of a long‑term survivor of anorectal melanoma who, seven years after APR surgery, developed a solitary rapidly growing tumor in the liver.

Correspondence to: Dr Yung‑Yeh Su, Department of Internal Case report Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Ziyou 1st Road, Sanmin, Kaohsiung 807, Taiwan, R.O.C. A 58‑year‑old Taiwanese male was diagnosed with malignant E‑mail: [email protected] melanoma of the anorectum and underwent APR at Kaohsiung Medical University Hospital (Kaosiung, Taiwan) in 2001. Key words: primary gastrointestinal stromal tumor of the liver, Microscopically, the anorectal tumor was composed of anorectal melanoma, imatinib, wild‑type tumor spindle‑shaped neoplastic cells beneath the squamous epithelium with brownish pigments and adjacent junctional activity. Furthermore, the tumor was immunohistochemically positive for human melanoma black (HMB‑45) and S‑100 (Fig. 2A‑D). SU et al: PRIMARY GASTROINTESTINAL STROMAL TUMOR OF THE LIVER 2367

No surgical margin or lymph node involvement was apparent, A therefore, stage I anorectal melanoma was diagnosed. The patient did not receive any adjuvant therapy and was regularly followed up by physical examination every two weeks at Kaoh- siung Medical University Hospital for five years after surgery. In 2009, after a further two years and at the age of 65 years, the patient presented to the Department of General Surgery at Kaohsiung Medical University Hospital with a two‑month history of general malaise, loss of appetite and progressively worsening dull pain over the epigastrium. An appropriate physical examination revealed no abnormalities, with the exception of the APR surgical scar on the abdominal wall. However, a follow‑up contrast‑enhanced computed tomography (CT) scan revealed a 12x11‑cm solitary tumor within the left lobe B of the liver (Fig. 1A). Serum α‑fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19‑9 levels were all within normal limits. Subsequently, a percutaneous CT‑guided biopsy of the liver tumor was performed. Microscopically, the liver tumor was composed of spindle cells arranged in interlacing fascicles with hyperchromatic, round or oval to spindle pleomorphic nuclei. Immunohistochemical (IHC) staining revealed that the neoplastic cells were diffusely and strongly positive for CD117, but negative for HMB‑45, S‑100 melan‑A and CD34. Furthermore, the mitotic activity of the tumor cells was five mitoses per 10 high‑power fields. Retrospectively, positive CD117 staining was also observed in the anorectal melanoma and the basal layer squamous epithelium. The results of the histological and IHC staining of the anorectal C melanoma are shown in Fig. 2A‑D, and the liver tumor in Fig. 2F‑I. In addition, polymerase chain reaction followed by direct sequencing was performed using DNA extracted from formalin‑fixed, paraffin‑embedded (FFPE) tissue, revealing that the anorectal melanoma and hepatic tumor were negative for BRAFV600E (data not shown). To confirm the diagnosis, transmission electron microscopy (TEM) of the FFPE‑derived tumors was performed to determine the ultrastructure of the two tumors. Analysis of the anorectal tumor showed a number of electron‑dense granules around the nucleus, which were considered to be atypical melanosomes, and inconspicuous microtubules within the cisternal space of the cytoplasm (Fig. 2E). These features were consid- Figure 1. (A) Initial CT scan indicating a heterogeneous contrast‑enhanced ered to correspond with the diagnosis of melanoma. Due to mass in the left hepatic lobe with left portal vein invasion at diag- damage of the fine structures of the small paraffin-embedded nosis. (B) CT scans three months after imatinib treatment (dose, 400 mg/day), and (C) two months after chemotherapy with doxorubicin (dose, 50 mg/m2) tissue during formalin fixation and subsequent xylene treat- 2 ment, artifacts were present in the sample and a collapsed and cisplatin (dose, 50 mg/m ). CT, computed tomography. cytoplasmic structure was observed. Thus, the quality of the liver TEM image was poor. Therefore, no villous cytoplasmic processes or dispersed intermediate filaments, which are hepatic GIST was considered as unresectable, therefore, oral considered to be characteristic ultrastructure features of imatinib was administered at a dose of 400 mg/day for two GISTs, could be identified (13). However, hyperchromatic months. However, a follow‑up CT scan after two months of nuclei and a vesicular cytoplasm without melanosomes were imatinib therapy demonstrated that the tumor had progressed present (Fig. 2J), indicating that the liver tumor may have a to 22x13 cm in size (Fig. 1B). While awaiting the approval of different histology from the prior melanoma. sunitinib from regulatory authorities, systemic chemotherapy Despite testing negative for KIT and PDGFRA mutations, consisting of 50 mg/m2 doxorubicin and 50 mg/m2 cisplatin was the liver tumor was diagnosed as primary GIST of the liver administered every three weeks for five months. This regimen based on its IHC profiling (diffusely strongly CD117‑positive, resulted in symptomatic improvement manifesting as a decrease and negative for HMB‑45 and S‑100), and TEM features in dull epigastric pain and tumor size by palpation after the when compared with anorectal melanoma, as well as the lack first cycle of treatment. Thus, this chemotherapeutic treatment of other intra‑abdominal tumors identified on abdominal CT strategy was continued. A follow‑up CT scan, conducted imaging. Due to the presence of left portal vein invasion, the two months later, demonstrated that the tumor had stabilized 2368 ONCOLOGY LETTERS 10: 2366-2370, 2015

A B

C D

E F

G H

I J

Figure 2. Histology: (A‑H) IHC analysis and (I and J) EM of the primary anorectal melanoma and second primary hepatic gastrointestinal stromal tumors. For the anorectal lesion, (A) H&E staining reveled subepithelial spindle neoplastic cells with brownish pigments (arrows), which were positive for (C) HMB45, (E) CD117 and (G) S‑100 in IHC analysis, and (I) positive for atypical melanosome in EM examination. For the hepatic lesion, (B) H&E staining revealed spindle neoplastic cells arranged in whorls or intervening fascicles, which were (D) negative for HMB45, (F) strongly positive for CD117 and (H) negative for S‑100 in IHC staining. (J) EM showed hyperchromatic nuclei and vesicular cytoplasm. IHC, immunohistochemical; H&E, hematoxylin and eosin; HMB‑45, human melanoma black‑45; CD117, cluster of differentiation 117; EM, electronic microscopy.

with minimal regression to a size of 19x11 cm (Fig. 1C). The was subsequently diagnosed as a second primary GIST of the chemotherapy was continued for an additional three months, liver by IHC. The patient had undergone APR for a stage I substituting with 37.5 mg/day sunitinib after disease progres- anorectal melanoma seven years prior. Clinically, it is not sion. However, the patient did not respond to sunitinib and possible to distinguish between a metastatic melanoma and succumbed to the disease one month later. a metastatic or primary GIST in the liver, as the two types of tumor can be hypervascular in the early arterial phase Discussion of a CT scan, and grow rapidly. Considering the history of anorectal melanoma and the absence of a KIT/PDGFRA muta- The current study describes the case of a unique patient who tion during genotyping, the diagnosis of GIST in the present was found to have a solitary hypervascular liver tumor that patient may be disputable. However, if the patient did not have SU et al: PRIMARY GASTROINTESTINAL STROMAL TUMOR OF THE LIVER 2369 b a history of mucosal melanoma, the tumor could be easily diagnosed as GIST based on the results of the CD117 staining, KIT PDGFRA status irrespective of its / genotyping. Therefore, a mutation PDGFRA 1 / final diagnosis of hepatic GIST was determined, based on the diffusely strong CD117 staining, negativity for HMB‑45 and KIT , exon 12 S100 (two positive markers noted in his anorectal melanoma) exon 1 PDGFRA PDGFRA / and the difference in ultrastructure between the two tumors, as KIT .

KIT noted by performing TEM. α Not performed Not performed Not performed PDGFRA Initially, the diagnosis of GIST was considered to be more favorable for the current patient compared with those exhibiting metastatic melanoma, with disease‑specific median survival

10 50 50 No 50 ‑ type 10 Wild periods of 19.0 and 13.3 months, respectively (14). However, / / / / / 1 5 4 20 75 index following the approval of imatinib in 2002, results indicated Mitotic that metastatic or unresectable GIST was more treatable compared with metastatic melanoma, with a notable increase in survival to 38.4‑60 months (according to the kinase geno- ‑ ‑ ‑ ‑ ‑ ‑

S100 type) (15). Imatinib markedly improved the survival of GIST patients, regardless of the KIT/PDGFR mutation status. Despite imatinib typically producing a poorer response in wild‑type GIST compared with exon 11‑mutated GIST, imatinib does + + + + + provide a benefit to patients with wild‑type GIST, exhibiting a disease control rate of >60% (15). Furthermore, in patients Vimentin with wild‑type GIST, Asian populations appear more likely to benefit from imatinib treatment compared with Western populations. In the CALGB 150105 study, clinical benefit rates were ‑ ‑ + + + + 78-95% in the Asian population and 64% in the Western popu- CD34 lation (15). Additionally, five-year survival rates of 60-70% and 40-45% were noted for Asian and Western populations, Immunohistochemical staining respectively (15-17). Although the differences may have been ‑ + + + + + caused by the small-size bias of Asian studies, the possibility

CD117 of higher pharmacokinetic parameters in Asian populations following fixed-dose imatinib treatment should also be considered. Despite the increased benefit in Asian populations, the

a current patient did not receive any benefit from imatinib treat- 20 18 12 15 5.1 ment and the tumor progressed rapidly within two months, Tumor size, cm which indicates that the nature of primary hepatic GIST may

cluster of differentiaion; PDGFRA, platelet‑derived growth factor receptor was analyzed. CD, cluster of differentiaion; be different from those arising in the alimentary tract. 1 To t h e b e s t of o u r k n owl e d ge, t o d a t e, o n ly five c a s e s of p r i m a r y hepatic GIST have been previously reported (Table I) (7‑11). exon 1 A mong t hese five cases, two cases received i mati n ib t herapy (8,9). Male Male Male Male Large Male Female Gender

KIT One of the imatinib‑treated cases lacked mutation analysis data, however, the patient exhibited a good response to imatinib, Only b resulting in a disease‑free status for three years (8). The other imatinib‑treated case had no mutation of KIT exon 11 (only KIT 17 70 37 30 65 79 exon 11 was analyzed) and responded well to imatinib, with

Age, years a long‑term survival period of nine years (9). As only a small number of cases of primary hepatic GIST have been reported thus far, the correlation between the KIT genotype and response to imatinib, a tyrosine kinase inhibitor, remains inconclusive;

thus, additional studies are required to address the issue. In conclusion, despite the poor response to imatinib of Cell type Spindle Epithelioid Spindle Mixed Spindle Spindle the primary hepatic KIT/PDGFRA wild‑type GIST in the current patient, the present study highlights the importance of considering a second primary malignancy and performing immunohistochemical analysis upon the occurrence of a newly (11) (8) developed lesions in long‑term remission cancer survivors. 9) ( et al

et al With the emergence of modern molecular technologies, such (10) (7) as next-generation sequencing, it may be possible to precisely et al

et al determine genetic alterations that exist between the two et al tumors. This may aid in determining the nature of the second Described as a large tumor, no exact dimensions provided. tumor, Described as a large Table I. Five cases of primary gastrointestinal stromal tumors the liver. Table ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ Author (Reference) Hu De Chiara Ochiai Luo Yamamoto Current case a 2370 ONCOLOGY LETTERS 10: 2366-2370, 2015 tumor (delayed recurrence versus second primary), as well as 9. Ochiai T, Sonoyama T, Kikuchi S, et al: Primary large gastrointestinal stromal tumor of the liver: report of a case. Surg providing useful information to guide therapeutic treatment of Today 39: 633‑636, 2009. the disease. 10. Luo XL, Liu D, Yang JJ, Zheng MW, Zhang J and Zhou XD: Primary gastrointestinal stromal tumor of the liver: a case report. World J Gastroenterol 15: 3704‑3707, 2009. References 11. Yamamoto H, Miyamoto Y, Nishihara Y, et al: Primary gastrointestinal stromal tumor of the liver with PDGFRA gene mutation. 1. Weinstock MA: Epidemiology and prognosis of anorectal Hum Pathol 41: 605‑609, 2010. melanoma. Gastroenterology 104: 174‑178, 1993. 12. Corless CL, Fletcher JA and Heinrich MC: Biology of gastroin- 2. Yeh JJ, Shia J, Hwu WJ, et al: The role of abdominoperineal testinal stromal tumors. J Clin Oncol 22: 3813‑3825, 2004. resection as surgical therapy for anorectal melanoma. Ann 13. Park SH, Kim MK, Kim H, et al: Ultrastructural studies Surg 244: 1012‑1017, 2006. of gastrointestinal stromal tumors. J Korean Med Sci 19: 3. Homsi J and Garrett C: Melanoma of the anal canal: a case series. 234‑244, 2004. Dis Colon Rectum 50: 1004‑1010, 2007. 14. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the 4. Aytac B, Adim SB, Yerci O and Yilmazlar T: Anorectal malignant American Joint Committee on Cancer staging system for melanomas: experience of Uludag University. Kaohsiung J Med cutaneous melanoma. J Clin Oncol 19: 3635-3648, 2001. Sci 26: 658‑662, 2010. 15. Heinrich MC, Owzar K, Corless CL, et al: Correlation of kinase 5. Ho MY and Blanke CD: Gastrointestinal stromal tumors: disease genotype and clinical outcome in the North American Intergroup and treatment update. Gastroenterology 140: 1372‑1376.e2, 2011. Phase III Trial of imatinib mesylate for treatment of advanced 6. Reith JD, Goldblum JR, Lyles RH and Weiss SW: gastrointestinal stromal tumor: CALGB 150105 Study by Cancer Extragastrointestinal (soft tissue) stromal tumors: an analysis of and Leukemia Group B and Southwest Oncology Group. J Clin 48 cases with emphasis on histologic predictors of outcome. Mod Oncol 26: 5360‑5367, 2008. Pathol 13: 577‑585, 2000. 16. Yeh CN, Chen TW, Lee HL, et al: Kinase mutations and imatinib 7. Hu X, Forster J and Damjanov I: Primary malignant gastroin- mesylate response for 64 Taiwanese with advanced GIST: testinal stromal tumor of the liver. Arch Pathol Lab Med 127: preliminary experience from Chang Gung Memorial Hospital. 1606‑1608, 2003. Ann Surg Oncol 14: 1123‑1128, 2007. 8. De Chiara A, De Rosa V, Lastoria S, et al: Primary gastrointestinal 17. Kim TW, Ryu MH, Lee H, et al: Kinase mutations and efficacy stromal tumor of the liver with lung metastases successfully treated of imatinib in Korean patients with advanced gastrointestinal with STI‑571 (imatinib mesylate). Front Biosci 11: 498‑501, 2006. stromal tumors. Oncologist 14: 540‑547, 2009.